Middle East Respiratory Syndrome Coronavirus Transmission - CDC

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  Middle East Respiratory Syndrome
      Coronavirus Transmission
               Marie E. Killerby, Holly M. Biggs, Claire M. Midgley, Susan I. Gerber, John T. Watson

                                                                    (Figure). MERS-CoV human cases result from primary
 Middle East respiratory syndrome coronavirus (MERS-
                                                                    or secondary transmission. Primary transmission is
 CoV) infection causes a spectrum of respiratory illness,
                                                                    classified as transmission not resulting from contact
 from asymptomatic to mild to fatal. MERS-CoV is
 transmitted sporadically from dromedary camels to humans           with a confirmed human MERS case-patient (15) and can
 and occasionally through human-to-human contact.                   result from zoonotic transmission from camels or from
 Current epidemiologic evidence supports a major role in            an unidentified source. Conzade et al. reported that,
 transmission for direct contact with live camels or humans         among cases classified as primary by the WHO, only 191
 with symptomatic MERS, but little evidence suggests                (54.9%) persons reported contact with dromedaries (15).
 the possibility of transmission from camel products or             Secondary transmission is classified as transmission
 asymptomatic MERS cases. Because a proportion of case-             resulting from contact with a human MERS case-
 patients do not report direct contact with camels or with          patient, typically characterized as healthcare-associated
 persons who have symptomatic MERS, further research is             or household-associated, as appropriate. However,
 needed to conclusively determine additional mechanisms
                                                                    many MERS case-patients have no reported exposure to
 of transmission, to inform public health practice, and to
                                                                    a prior MERS patient or healthcare setting or to camels,
 refine current precautionary recommendations.
                                                                    meaning the source of infection is unknown. Among
                                                                    1,125 laboratory-confirmed MERS-CoV cases reported
M     iddle East respiratory syndrome (MERS) coro-
      navirus (MERS-CoV) was first detected in Sau-
di Arabia in 2012 (1). To date, >2,400 cases globally
                                                                    to WHO during January 1, 2015–April 13, 2018, a total
                                                                    of 157 (14%) had unknown exposure (15).
                                                                         Although broad categories of exposure are
have been reported to the World Health Organiza-                    associated with transmission (e.g., exposure to camels
tion (WHO), including >850 deaths (case fatality rate               or to healthcare facilities with ill patients), exact
≈35%) (2). Illness associated with MERS-CoV infec-                  mechanisms of MERS-CoV transmission are not fully
tion ranges from asymptomatic or mild upper respi-                  understood. Little direct epidemiologic evidence
ratory illness to severe respiratory distress and death.            exists regarding transmission routes or the efficacy
    MERS-CoV is a zoonotic virus, and dromedary                     of interventions in reducing transmission. However,
camels are a reservoir host (3–5). Bats are a likely                other potentially important factors, including
original reservoir; coronaviruses similar to MERS-                  detection of virus in different secretions, detection and
CoV have been identified in bats (6), but epidemiologic             survival of virus in the environment, and detection
evidence of their role in transmission is lacking.                  of virus in aerosols, lend support for the biological
Infection of other livestock species with MERS-CoV                  plausibility of certain transmission pathways.
is possible (7); however, attempts to inoculate goats,              We summarize the available evidence regarding
sheep, and horses with live MERS-CoV did not                        camel-to-camel, camel-to-human, and human-to-
produce viral shedding (8), and no epidemiologic                    human transmission of MERS-CoV, including direct
evidence has implicated any species other than                      epidemiologic evidence and evidence supporting
dromedaries in transmission.                                        biologically plausible transmission routes.
    Sporadic zoonotic transmission from dromedaries
has resulted in limited human-to-human transmission
                                                                    MERS-CoV in Camels
chains, usually in healthcare or household settings (9–14)
                                                                    Evidence for Infection of Camels
Author affiliation: Centers for Disease Control and Prevention,     MERS-CoV infection in camels has been demon-
Atlanta, Georgia, USA                                               strated through serologic investigations, molecular
DOI: https://doi.org/10.3201/eid2602.190697                         evidence using real-time reverse transcription PCR

                            Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 2, February 2020               191
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Figure. Summary of Middle East respiratory syndrome coronavirus transmission pathways. Solid lines indicate known transmission
pathways; dashed lines indicate possible transmission pathways for which supporting evidence is limited or unknown.

(rRT-PCR), and by virus isolation, as described in                 introduced via calf saliva or nasal secretions or fecal
recent reviews (16,17). Geographically wide-ranging                contamination. Experimentally introduced virus can
seroprevalence studies have identified MERS-CoV–                   survive in milk but did not survive when heat treated
specific antibodies in camels in countries across the              (28). It is also not known if the virus would remain vi-
Middle East and North, West, and East Africa, often                able in milk from seropositive dams when antibodies
with >90% seroprevalence in adult camels (18). Stud-               could be found in the milk.
ies in many of these countries have shown molecular                     These shedding data indicate that contact with
evidence of MERS-CoV RNA and isolation of infec-                   camel nasal secretions, saliva, and respiratory
tious MERS-CoV in camels (16,17,19–21).                            droplets carry potential risk for camel-to-human
                                                                   or camel-to-camel transmission. Contact with
Viral Shedding in Camels                                           nasal secretions can occur when directly handling
In naturally or experimentally infected camels,                    live camels, and virus from camel nasal secretions
MERS-CoV appears to cause an upper respiratory                     can contaminate fomites in the environment (29).
tract infection with or without symptoms, includ-                  Although rRT-PCR evidence of MERS-CoV and
ing nasal and lachrymal discharge, coughing, sneez-                genome fragments have been detected in air samples
ing, elevated body temperature, and loss of appetite               from a camel barn (30), no live virus was detected,
(20,22,23). In naturally infected camels, MERS-CoV                 and no epidemiologic study has implicated airborne
RNA has been recovered most commonly from na-                      transmission. Transmission following exposure to
sal swabs but also from fecal swabs, rectal swabs,                 camel feces may be biologically plausible, although
and lung tissue (20,24). No evidence of viral RNA has              no epidemiologic evidence indicates the likelihood of
been demonstrated in camel serum, blood, or urine                  such transmission. Similarly, although transmission
using rRT-PCR (25,26). In experimentally infected                  following consumption of raw camel milk may
camels, infectious virus and RNA was detected in na-               be biologically plausible, epidemiologic studies
sal swab and oral samples but not in blood, serum, fe-             have not consistently identified milk consumption
ces, or urine (23). MERS-CoV RNA has been detected                 as a unique risk factor for MERS-CoV infection
in raw camel milk collected using traditional milking              or illness, independent of other direct or indirect
methods, including using a suckling calf as stimu-                 camel exposures (31,32). No epidemiologic evidence
lus for milk letdown; presence of live virus was not               supports transmission associated with camel urine
evaluated (27). Viral RNA may therefore have been                  or meat.

192                        Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 2, February 2020
MERS-CoV Transmission

Camel-to-Camel Transmission Dynamics                           including age, smoking, handwashing after camel
MERS-CoV RNA is detected most frequently in                    contact, consuming camel meat or milk, or specific
younger camels (22,25,33) but has been detected in             occupation (camel truck driver, handler, or herder)
camels >4 years of age (22). In a longitudinal study of        (47). Neither investigation controlled for possible
a camel dairy herd, most calves became infected with           confounding risk factors (e.g., age or duration of
MERS-CoV at 5–6 months of age, around the time ma-             exposure to camels). In Abu Dhabi, an investigation
ternal MERS-CoV antibodies wane. The calves then               of 235 market and slaughterhouse workers showed
produced MERS-CoV antibodies by 11–12 months of                that 17% were seropositive for MERS-CoV and that
age (34). In seroprevalence studies, camels 2 years of age (25,35). Across many countries, the se-        factors for seropositivity (32). Among market workers
roprevalence of adult camels is >90% (16,17). Overall,         in the same study, handling live camels and either
these data suggest most camels are initially infected          cleaning equipment (e.g., halters, water troughs, etc.)
with MERS-CoV at
PERSPECTIVE

to camels (Appendix reference 52). MERS-CoV se-                 associated outbreaks have provided most of the con-
quences from camels in Africa phylogenetically cluster          text for investigation of risk factors for human-to-
separately relative to camel and human MERS-CoV                 human transmission.
from the Arabian Peninsula, suggesting single or few
introductions into Saudi Arabia and limited contact             Viral Shedding in Humans
(19). Differences in virus growth have been shown be-           MERS-CoV shedding in humans appears to dif-
tween MERS-CoV strains isolated from West Africa                fer from the pattern of viral shedding in camels. In
and those isolated from the Middle East (19); relative          humans, MERS-CoV RNA and live virus have been
to human and camel MERS-CoV from Saudi Arabia,                  detected in both upper (nasopharyngeal and oropha-
virus isolates from Burkina Faso and Nigeria had low-           ryngeal swab) and lower (sputum, tracheal aspirate,
er virus replication competence in ex vivo cultures of          and bronchoalveolar lavage fluid) respiratory tract
human bronchus and lung. These findings may sug-                samples, although RNA levels are often higher in
gest regional variation in the potential for MERS-CoV           the lower respiratory tract (Appendix reference 61).
replication in humans. Other factors contributing to            In humans, MERS-CoV is predominantly thought to
the limited evidence of zoonotic MERS transmission in           infect the lower respiratory tract (Appendix reference
Africa may include differences between virus surveil-           62), where the MERS-CoV dipeptidyl peptidase-4
lance, human populations, camel populations, camel              (DPP4) receptor predominates, in contrast to camels,
husbandry, and the type of human–camel interactions             where DPP4 is found predominantly in the upper re-
in these regions.                                               spiratory tract (Appendix reference 63). More severe-
                                                                ly ill patients typically have higher MERS-CoV RNA
Prevention of Zoonotic Transmission                             levels, as indicated by rRT-PCR cycle threshold (Ct)
WHO recommends that anyone presumed at higher                   values and more prolonged viral shedding (Appen-
risk for severe illness (e.g., persons who are older, have      dix reference 64). MERS-CoV RNA has been detected
diabetes, or are immunocompromised) should avoid                from the lower respiratory tract >1 month after illness
contact with camels and raw camel products (Appen-              onset (Appendix references 65,66), and live virus has
dix reference 53). Although no evidence definitively            been isolated up to 25 days after symptom onset (Ap-
links raw camel products with MERS-CoV infection,               pendix reference 67). RNA detection is prolonged in
WHO presents these precautions in the context of con-           the respiratory tract of patients with diabetes mellitus,
siderable knowledge gaps surrounding MERS-CoV                   even when adjusting for illness severity (Appendix
transmission. In addition, WHO recommends basic                 reference 66). Among mildly ill patients, who might
hygiene precautions for persons with occupational ex-           typically be isolated at home, viral RNA levels in the
posure to camels (Appendix reference 53).                       upper respiratory tract have been detected for several
                                                                weeks (Appendix references 68,69). Infectious virus
Human-to-Human Transmission                                     has been isolated from the upper respiratory tract of a
After zoonotic introduction, human-to-human trans-              patient with mild symptoms (Appendix reference 68),
mission of MERS-CoV can occur, but humans are                   suggesting a potential for transmission among less
considered transient or terminal hosts (40), with no            severely ill patients. However, there is no definitive
evidence for sustained human-to-human community                 evidence of transmission from asymptomatic cases,
transmission. In addition to limited household trans-           and epidemiologic evidence suggests that transmis-
mission, large, explosive outbreaks in healthcare set-          sion from mildly symptomatic or asymptomatic cases
tings have been periodically documented. In South               does not readily occur (Appendix reference 70).
Korea in 2015, a single infected traveler returning                  In humans, MERS-CoV RNA has been detected
from the Arabian Peninsula was linked to an out-                outside of the respiratory tract (Appendix references
break of 186 cases, including 38 deaths (case-fatality          66,71,72). Viral RNA has been detected in the whole
rate 20%) (Appendix reference 54). Multiple other               blood or serum of mildly or severely ill patients (Ap-
healthcare-associated outbreaks have been described             pendix references 66,72) and in the urine of patients
in Saudi Arabia (Appendix references 55,56), Jordan             who subsequently died (Appendix reference 66), al-
(Appendix reference 57), and United Arab Emirates               though virus isolation attempts on urine samples (Ap-
(Appendix reference 58). Healthcare transmission                pendix reference 66) and serum (Appendix reference
has also occurred outside the Arabian Peninsula                 71) have been unsuccessful. MERS-CoV RNA has also
from exported cases, including in the United King-              been detected from the stool of mildly and severely ill
dom (Appendix reference 59) and France (Appendix                patients (Appendix reference 66). Subgenomic MERS-
reference 60). Given their size and scope, healthcare-          CoV RNA, an intermediate in the virus replication

194                     Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 2, February 2020
MERS-CoV Transmission

cycle, has been detected in stool, suggesting that             not wearing an N95 respirator. All 20 healthcare
MERS-CoV might replicate in the gastrointestinal tract         workers had been in the same room or automobile
(Appendix reference 73); however, it is not clear if this      or within 2 m of a MERS patient. This study provid-
contributes to pathogenesis or transmission.                   ed evidence to suggest that aerosol transmission of
                                                               MERS-CoV may be possible at close range, as seen
Reproduction Number and Attack Rates                           with other respiratory viruses (e.g., influenza) spread
The number of secondary cases resulting from a single          primarily by droplet or contact transmission, particu-
initial case (reproduction number, R0) (Appendix ref-          larly during aerosol-generating procedures. Having
erence 74) ranges widely for MERS-CoV, e.g., from 8.1          participated in infection control training specific to
in the South Korea outbreak, compared with an over-            MERS-CoV was associated with a decreased risk for
all R0 of 0.45 in Saudi Arabia (Appendix reference 74).        seropositivity; in healthcare workers in South Korea,
Superspreading events, which generally describe a              a lack of personal protective equipment (PPE) use
single MERS-CoV case epidemiologically linked to >5            was more likely in MERS-CoV–infected healthcare
subsequent cases, have been frequently described, par-         workers than among exposed uninfected healthcare
ticularly in healthcare-associated outbreaks (Appendix         workers (Appendix reference 78).
references 55,56). R0 estimates, however, can vary de-              Studies have shown infection among persons
pending on numerous biologic, sociobehavioral, and             without close and prolonged exposure to MERS case-
environmental factors, and must be interpreted with            patients during healthcare-associated outbreaks. In
caution (Appendix reference 75). Most studies estimat-         Jeddah during 2014, a total of 53 healthcare-associat-
ing R0 across multiple areas, or at the end stage of an        ed cases were reported among hospitalized patients,
outbreak, result in estimates of R0
PERSPECTIVE

potential MERS cases in areas with local MERS-CoV              has been described in Saudi Arabia in camels (48) and
transmission (e.g., Arabian Peninsula) is challenging          humans (Appendix references 88,89) but no substan-
because signs and symptoms are often nonspecific               tial change in human epidemiology was seen with this
(Appendix reference 83). In addition, complications            circulating variant (Appendix reference 89). Deletion
or exacerbations of concurrent conditions, including           variants of MERS-CoV were identified in humans in
chronic kidney or heart disease, can manifest with             Jordan (Appendix reference 57), also without notable
acute or worsening respiratory symptoms that de-               changes in epidemiology (Appendix reference 80).
lay suspicion for MERS. Patient crowding has been
associated with transmission in healthcare facilities,         Conclusions
particularly in emergency departments (Appendix                In areas in which MERS-CoV actively circulates
references 54,79). In multiple outbreaks, inconsistent         among camels, human cases can result from zoonotic
PPE use has been reported as contributing to trans-            transmission. In these areas, close contact with camels
mission (Appendix references 56,58), and transmis-             (e.g., handling or training) is an identified risk factor
sion to healthcare personnel despite reported use of           for infection. Direct or indirect contact with nasal se-
appropriate PPE (Appendix references 56,78) sug-               cretions probably plays a role. Given limited knowl-
gests that improper PPE use may contribute to trans-           edge of mechanisms of MERS-CoV transmission, cur-
mission. Transmission risk may be particularly high            rent precautions to prevent zoonotic transmission,
during aerosol-generating procedures, in which large           such as recommendations to avoid consumption of
quantities of virus might be aerosolized.                      raw camel milk and meat, are prudent despite the
                                                               lack of epidemiologic evidence linking these expo-
Household Transmission                                         sures to MERS-CoV infec-tion. Such precautionary
Human-to-human transmission of MERS-CoV has                    recommendations, while appropriate in the context
been reported among household contacts. Drosten et             of limited knowledge, should not be interpreted as
al. described 12 probable cases among 280 household            evidence of an epidemiologic association with MERS-
contacts of 26 index case-patients (13). Arwady et al.         CoV transmission.
investigated MERS-CoV infections in an extended                     Human-to-human transmission of MERS-CoV
family of 79 relatives, of whom 19 (24%) tested positive       most frequently occurs following close contact with
for MERS-CoV by rRT-PCR or serology (Appendix ref-             MERS patients, predominantly in healthcare settings
erence 84). Risk factors for acquisition included sleep-       and less frequently in household settings. Specifically,
ing in an index case-patient’s room and touching their         contact with respiratory secretions, whether through
secretions. A study of MERS-CoV infection in a group           direct contact or through aerosolization of secretions
of expatriate women housed in a dormitory in Riyadh,           during aerosol-generating procedures, plays a
Saudi Arabia, showed an overall infection attack rate of       role in transmission. Virus isolation from fomites
2.7% (Appendix reference 85). Risk factors for infection       suggests the potential for alternative mechanisms
include direct contact with a confirmed case-patient           of transmission, but direct epidemiologic evidence
and sharing a room with a confirmed case-patient; a            is lacking. Although MERS-CoV has been isolated
protective factor was having an air conditioner in the         from a mildly ill case-patient, available evidence is
bedroom. However, transmission among household                 not sufficient to conclusively state that asymptomatic
contacts is variable; Hosani et al. found that none of         patients play an appreciable role in MERS-CoV
105 household contacts of 34 MERS-CoV case-patients            transmission. Given the knowledge gaps surrounding
showed antibodies to MERS-CoV (Appendix reference              transmission from asymptomatic patients, WHO
70). Among those 34 patients, 31 were asymptomatic             recommendations state “until more is known,
or mildly symptomatic, suggesting a lower risk for             asymptomatic RT-PCR positive persons should be
transmission among this group.                                 isolated, followed up daily for development of any
                                                               symptoms, and tested at least weekly—or earlier,
Viral Factors Affecting Human-to-Human Transmission            if symptoms develop—for MERS-CoV” (Appendix
No evidence has been reported that mutations or re-            reference 90). Available evidence supports published
combinations in MERS-CoV have led to changes in hu-            Centers for Disease Control and Prevention guidance
man-to-human transmission. Recombination has been              for infection prevention and control for hospitalized
documented among coronaviruses (Appendix refer-                MERS patients (Appendix reference 91).
ence 86) and has been linked to increasing pathogenic-              Large, explosive MERS-CoV outbreaks have
ity in strains of other animal RNA viruses (Appendix           repeatedly resulted in devastating impacts on
reference 87). Circulation of recombinant MERS-CoV             health systems and in settings where transmission

196                    Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 26, No. 2, February 2020
MERS-CoV Transmission

most frequently occurs. Sporadic community cases                              hospital in Saudi Arabia. Infect Control Hosp Epidemiol.
continue to be reported, and a small but consistent                           2016;37:1147–55. https://doi.org/10.1017/ice.2016.132
                                                                        11.   Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA,
proportion of MERS cases have no camel, healthcare,                           Cummings DA, et al.; KSA MERS-CoV Investigation
or MERS-CoV exposure. Continuous epidemiologic                                Team. Hospital outbreak of Middle East respiratory
and virologic monitoring is required to determine                             syndrome coronavirus. N Engl J Med. 2013;369:407–16.
other exposures resulting in transmission and to                              https://doi.org/10.1056/NEJMoa1306742
                                                                        12.   Oboho IK, Tomczyk SM, Al-Asmari AM, Banjar AA,
assess for the possibility of improved virus fitness                          Al-Mugti H, Aloraini MS, et al. 2014 MERS-CoV outbreak
and adaptation. Until additional evidence is available                        in Jeddah—a link to health care facilities. N Engl J Med.
to further refine recommendations to prevent                                  2015;372:846–54. https://doi.org/10.1056/NEJMoa1408636
MERS-CoV transmission, continued use of existing                        13.   Drosten C, Meyer B, Müller MA, Corman VM, Al-Masri M,
                                                                              Hossain R, et al. Transmission of MERS-coronavirus in
precautionary recommendations is necessary.                                   household contacts. N Engl J Med. 2014;371:828–35.
                                                                              https://doi.org/10.1056/NEJMoa1405858
About the Author                                                        14.   Memish ZA, Zumla AI, Al-Hakeem RF, Al-Rabeeah AA,
                                                                              Stephens GM. Family cluster of Middle East respiratory
Dr. Killerby is an epidemiologist in the Division of Viral                    syndrome coronavirus infections. N Engl J Med.
Diseases, National Center for Immunization and Respiratory                    2013;368:2487–94. https://doi.org/10.1056/NEJMoa1303729
Diseases, Centers for Disease Control and Prevention. Her               15.   Conzade R, Grant R, Malik MR, Elkholy A, Elhakim M,
                                                                              Samhouri D, et al. Reported direct and indirect contact with
research interests include respiratory viruses, such as
                                                                              dromedary camels among laboratory-confirmed MERS-CoV
MERS-CoV, human coronaviruses, and adenoviruses.                              cases. Viruses. 2018;10:425. https://doi.org/10.3390/v10080425
                                                                        16.   Sikkema RS, Farag EABA, Islam M, Atta M, Reusken CBEM,
                                                                              Al-Hajri MM, et al. Global status of Middle East respiratory
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